Growing neurons must recognize and follow specific pathways to their synaptic targets by sensing guidance cues that regulate cell motility. In Drosophila, the Drl receptor is expressed by a subset of neurons and is required for proper axon pathfinding. Drl is a member of the Ryk family of atypical receptor tyrosine kinases (RTKs), which are catalytically inactive receptors for Wnt ligands. Wnt ligands, which typically function in signaling pathways distinct from RTKs, are involved in multiple disease processes such as cancer cell nvasiveness and metastasis. The human Drl ortholog, Ryk, has also been implicated in numerous cancers. Yet, little is known about the signaling events initiated by Ryk family receptors in response to Wnts. The broader goal of this proposal is to identify and characterize the signaling pathways employed by Drl and Wnt proteins to regulate cell motility. Drl signaling activity will be elucidated using proteomic, cell-biological, and genetic approaches to 1) Analyze the Drl cytoplasmic domain for functional regions, 2) Investigate the role Drl ntramembrane proteolysis and the function of the released Drl cytoplasmic domain, 3) Identify Drl binding proteins, and 4) Characterize Drl-binding proteins and candidate Drl signaling effectors.